RECOGNITION OF BETA-2-MICROGLOBULIN-NEGATIVE (BETA-2M-) T-CELL BLASTS BY NATURAL-KILLER-CELLS FROM NORMAL BUT NOT FROM BETA-2M- MICE - NONRESPONSIVENESS CONTROLLED BY BETA-2M- BONE-MARROW IN CHIMERIC MICE

The role of major histocompatibility complex (MHC) class I expression in control of the sensitivity of normal cells to natural killer (NK) cells was studied by the use of mutant mice made deficient for expression of beta-2-microglobulin (beta-2m) through homologous recombination in embryonal stem cells. T-cell blasts from beta-2m-deficient (beta-2m -/-) mice were killed by NK cells from normal mice in vitro, while beta-2m +/-blasts were resistant. The beta-2m defect also affected the NK effector cell repertoire: NK cells from beta-2m -/- mice failed to kill beta-2m -/- blasts, while they retained the ability to kill the prototype NK cell target lymphoma YAC-1, although at reduced levels. The inability to recognize beta-2m -/- blasts could be transferred with beta-2m -/- bone marrow to irradiated beta-2m-expressing mice. In contrast, the development of CD8+ T cells (deficient in beta-2m -/- mice) was restored in such chimera. These results indicate that loss of MHC class I/beta-2m expression is sufficient to render normal cells sensitive to NK cells, and that the same defect in the hemopoietic system of a mouse renders its NK cells tolerant to beta-2m-deficient but otherwise normal cells. In the beta-2m -/- mice, NK cells may be selected or educated by other bone marrow cells to tolerate the MHC class I deficiency. Alternatively, the specificity may be controlled directly by the class I molecules on the NK cells themselves.